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Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer’s Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models

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Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus—a complex brain structure with a pivotal role in learning and memory—is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice—a model of AD—and to determine the impact of Aβ40 and Aβ42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood–brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aβ40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aβ42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer’s disease.

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Data Availability

The data and material are available upon request to the corresponding author.

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Acknowledgements

The authors would like to express their special gratitude to Dr Kwang Sik Kim, John Hopkins University for generously donating the HBMEC cells to our research group. We deeply mourn his recent passing and appreciate his invaluable contribution. We would also like to thank Dr. María Cruz Miraglia and Dr. Guillermo Giambartolomei from the Institute of Immunology, Genetics, and Metabolism at CONICET for their support and collaboration.

Funding

This work was supported by Williams, René Barón and Florencio Fiorini Foundations, ANPCyT PICT Grants: 2016–1046 FS, 2016–1572 JB, 2019–03419 FS, PICT 2019–03928 ÁV, 2019–03692 JB, 2021–0509 CP and UBACyT 2018 Grant. The funding sources had no involvement in the study design nor the collection, analysis and interpretation of data. JP, CO, MB, and AG are recipients of CONICET PhD Fellowships, Argentina.

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Authors and Affiliations

  1. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina

    C. Pomilio, J. Presa, C. Oses, A. Vinuesa, M. Bentivegna, A. Gregosa, V. Levi, J. Beauquis & F. Saravia

  2. Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina

    C. Pomilio, J. Presa, A. Vinuesa, M. Bentivegna, A. Gregosa, J. Beauquis & F. Saravia

  3. FLENI, Instituto de Investigaciones Neurológicas Dr Raúl Carrea, Buenos Aires, Argentina

    M. Riudavets & G. Sevlever

  4. Department of Biochemistry and Molecular Biology and Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences, Oklahoma City, OK, 73104, USA

    V. Galvan

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Contributions

CP, JB, and FS conceived the studies and secured funding; CP, JP, JB, and FS designed and performed or supervised the performance of the experiments; CP, JP, CO, AV, MB, and AG analyzed the data; MR and GS provided the post mortem human samples; CP, JP, CO, VL, JB, and FS wrote and/or edited the manuscript. CP, VL, JB, and FS are CONICET Researchers.

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Correspondence to F. Saravia.

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Human brain post-mortem samples were obtained from the Biobank of the Instituto de Investigaciones Neurológicas Dr. Raúl Carrea, FLENI (http://www.fleni.org.ar/investigacion-educacion/investigacion-2/biobancos/) Buenos Aires, Argentina. FLENI’s Biobank participates in the global Alzheimer’s Disease Neuroimage Initiative (ADNI) and works in a collaborative and network-like manner with other brain banks in the world, only with scientific and altruistic purposes. The Biobank supplied brain specimens, anonymized antemortem information, and postmortem diagnosis. Informed consent of pre-donors authorizing the use of brain samples for research purposes was obtained by qualified personnel from the Instituto de Investigaciones Neurológicas Dr. Raúl Carrea and approved by the Institutional Ethics Committee (https://www.fleni.org.ar/investigacion-educacion/ceib/). No separate institutional approval was required.

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Pomilio, C., Presa, J., Oses, C. et al. Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer’s Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-023-03897-5

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